What is the differential diagnosis and recommended work‑up for a patient with urinalysis showing negative leukocytes, negative nitrite, normal urobilinogen, protein 1+, blood 3+, specific gravity 1.025, pH 6.0, and clear yellow urine?

Differential Diagnosis and Work-Up for Hematuria with Proteinuria in Clear Urine

Primary Differential Diagnosis

The most likely diagnosis is non-glomerular hematuria (urologic source) given the isolated blood 3+ with minimal proteinuria (1+), absence of pyuria, and clear urine appearance. 1

Key Diagnostic Considerations:

• Glomerular causes (glomerulonephritis, IgA nephropathy) typically present with dysmorphic RBCs, RBC casts, and significant proteinuria (≥2+), none of which are present here 2, 3
• Non-glomerular hematuria from urologic sources (stones, malignancy, trauma, infection) shows isomorphic RBCs without casts and minimal-to-no proteinuria 2, 3
• Exercise-induced hematuria resolves within 48-72 hours of rest and requires no further work-up if transient 2
• Menstrual contamination is the most common cause of isolated hematuria in women of reproductive age with clear urine 2, 3

Critical Interpretation of This Urinalysis

Why This Is NOT a Urinary Tract Infection:

• Negative leukocyte esterase + negative nitrite effectively rule out bacterial UTI with 90.5% negative predictive value 1, 4
• Absence of pyuria (0 WBC) has 82-91% negative predictive value for excluding infection 1
• Clear urine appearance argues strongly against infection, as pyuria typically causes cloudiness 2
• UTI requires BOTH pyuria (≥10 WBC/HPF) AND acute urinary symptoms (dysuria, frequency, urgency, fever >38.3°C, gross hematuria); this patient has neither 1, 4

Protein 1+ Significance:

• Protein 1+ (30 mg/dL) in the presence of blood 3+ and specific gravity 1.025 is likely a false-positive caused by hematuria and concentrated urine 5
• High specific gravity ≥1.020 is the strongest predictor of false-positive proteinuria on dipstick, with >10% increase in false readings 5
• Hematuria ≥3+ independently causes false-positive protein readings through hemoglobin interference with the dipstick reagent 5
• True proteinuria requires confirmation with albumin-to-creatinine ratio (ACR) when confounding factors are present 5

Mandatory Initial Work-Up

Immediate Steps:

1. Obtain a detailed history focusing on:

   • Timing relative to menstrual cycle (most common cause in women) 2, 3
   • Recent vigorous exercise or trauma 2
   • Gross hematuria episodes, flank pain, or dysuria 1
   • Smoking history, occupational chemical exposure, chronic catheter use (malignancy risk factors) 1
   • Family history of kidney disease, hearing loss, or hematuria (hereditary nephritis) 2

2. Repeat urinalysis with proper collection:

   • Midstream clean-catch specimen avoiding menstruation 1, 2
   • Process within 1 hour at room temperature or refrigerate within 4 hours 1, 6
   • Request microscopic examination for RBC morphology and casts 6, 2

3. Confirm proteinuria with ACR:

   • Order spot urine albumin-to-creatinine ratio to distinguish true proteinuria from dipstick artifact 5
   • ACR >30 mg/g indicates clinically significant proteinuria requiring nephrology evaluation 5

Age-Stratified Imaging Protocol:

• Patients <35 years with isolated microscopic hematuria and no risk factors: Defer imaging if hematuria resolves on repeat testing within 6 weeks 1
• Patients ≥35 years OR any age with risk factors (smoking, chemical exposure, chronic catheter): Obtain CT urography or renal ultrasound + cystoscopy to exclude malignancy (30-40% association) 1
• Persistent hematuria >6 weeks after initial detection: Mandatory urologic referral for CT urography and cystoscopy 1

Common Pitfalls to Avoid

• Do NOT treat empirically with antibiotics based on hematuria alone without pyuria and symptoms; this represents overtreatment of non-infectious hematuria 1, 4
• Do NOT assume protein 1+ indicates kidney disease when blood 3+ and high specific gravity are present; confirm with ACR 5
• Do NOT order urine culture when leukocyte esterase and nitrite are both negative and the patient is asymptomatic; culture adds no value 1, 6
• Do NOT dismiss hematuria as "contamination" without proper repeat testing; 30-40% of gross hematuria in adults ≥35 years is associated with malignancy 1
• Do NOT delay urologic evaluation if hematuria persists beyond 6 weeks or the patient has malignancy risk factors 1

Quality of Life Considerations

• Unnecessary antibiotic treatment for non-infectious hematuria causes harm through antimicrobial resistance, adverse drug effects, and Clostridioides difficile infection without clinical benefit 1
• Delayed diagnosis of urologic malignancy significantly worsens prognosis; early detection through appropriate imaging and cystoscopy is critical for morbidity and mortality reduction 1
• False-positive proteinuria leads to unnecessary nephrology referrals and patient anxiety; confirming with ACR prevents this cascade 5